Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is over-active/over-expressed in the majority of cancers of epithelial origin (Hynes N E, et al., ERBB receptors and cancer: the complexity of targeted inhibitors, Nature Reviews Cancer, 5(5):341-354 (2005)). Inhibition of the tyrosine kinase activity of EGFR has been the principle strategy of EGFR based cancer therapies. However, targeting EGFR by small molecule inhibitors of receptor tyrosine kinase has not produced satisfactory therapeutic efficacy. The general response rates are between 10-20% across a variety of human malignancies (Weiss J., First line erlotinib for NSCLC patients not selected by EGFR mutation: keep carrying the TORCH or time to let the flame die? Transl. Lung Cancer Res., 1(3):219-223 (2012); Cohen S J, et al., Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma, J. Clinical Oncology, 21(7):1301-1306 (2003); Dancey J E, et al., Targeting epidermal growth factor receptor—are we missing the mark?, Lancet 362(9377):62-64 (2003)). In other words, there is major population of cancer patients that do not respond to EGFR tyrosine kinase inhibitors. For example, although EGFR is over-expressed in more than 80% of late stage prostate cancers and negatively correlates with prognosis, prostate cancer is resistant to EGFR inhibitors (Hernes E., et al., Expression of the epidermal growth factor receptor family in prostate carcinoma before and during androgen-independence, British J. Cancer, 90(2):449-454 (2004); Pu Y S, et al., Epidermal growth factor receptor inhibitor (PD168393) potentiates cytotoxic effects of paclitaxel against androgen-independent prostate cancer cells, Biochemical Pharmacology, 71(6):751-760 (2006); Sherwood E R, et al., Epidermal growth factor-related peptides and the epidermal growth factor receptor in normal and malignant prostate, World J. Urology, 13(5):290-296 (1995); Zellweger T., et al., Expression patterns of potential therapeutic targets in prostate cancer, International J. Cancer, 113(4):619-628 (2005); Canil C M, et al., Randomized phase II study of two doses of gefitinib in hormone-refractory prostate cancer: a trial of the National Cancer Institute of Canada—Clinical Trials Group, J. Clinical Oncology, 23(3):455-460 (2005); Gross M, et al., A phase II trial of docetaxel and erlotinib as first-line therapy for elderly patients with androgen-independent prostate cancer, BMC Cancer 7:142 (2007)).
Evidence indicates that EGFR possesses tyrosine kinase independent functions. For example, EGFR knockout animals die soon after birth (Threadgill D W, et al., Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype, Science, 269(5221):230-234 (1995). However, mice with severely compromised EGFR tyrosine kinase activity are completely viable and display only some epithelial defects (Luetteke N C, et al., The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase, Genes & Development, 8(4):399-413 (1994)). As another example, both a wild type and a kinase-dead EGFR enhanced the survival of EGFR negative 32D hematopoietic cells (Ewald J A, et al., Ligand- and kinase activity-independent cell survival mediated by the epidermal growth factor receptor expressed in 32D cells, Experimental Cell Research 282(2):121-131 (2003). It has also been discovered that EGFR participates in the maintenance of basal intracellular glucose level of cancer cells by interacting with and stabilizing the sodium-glucose co-transporter 1 (SGLT1), independent of EGFR tyrosine kinase activity (Weihua Z, et al., Survival of cancer cells is maintained by EGFR independent of its kinase activity, Cancer Cell, 13(5):385-393 (2008)).
SGLT1 is an active glucose transporter that relies on extracellular sodium concentration to transport glucose into cells independent of glucose concentration (Wright E M, et al., Biology of human sodium glucose transporters, Physiological Reviews, 91(2):733-794 (2011). SGLT1 plays a critical role in glucose absorption and retention in the body (Castaneda-Sceppa C, et al., Sodium-dependent glucose transporter protein as a potential therapeutic target for improving glycemic control in diabetes, Nutrition Reviews, 69(12):720-729 (2011)). One of the hallmarks of cancer is that cancer cells exhibit altered energy metabolism, i.e. cancer cells consume a substantially higher amount of nutrients and energy substrates than their normal counterparts (Hanahan D, et al., Hallmarks of cancer: the next generation, Cell, 144(5):646-674 (2011). This enhanced energy consumption demands a high rate of nutrients uptake, which is achieved by over-expression of plasma membrane transporters (Ganapathy V, et al., Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond, Pharmacology & Therapeutics 121(1):29-40 (2009). Studies have found that SGLT1 is over-expressed in various types of cancers including ovarian carcinoma, oral squamous cell carcinoma, colorectal cancer, pancreatic cancer, and prostate cancer (Lai B, et al., Overexpression of SGLT1 is correlated with tumor development and poor prognosis of ovarian carcinoma, Archives of Gynecology and Obstetrics, 285(5):1455-1461 (2012); Hanabata Y, et al., Coexpression of SGLT1 and EGFR is associated with tumor differentiation in oral squamous cell carcinoma, Odontology/the Society of the Nippon Dental University, 100(2):156-163 (2012); Guo G F, et al., Overexpression of SGLT1 and EGFR in colorectal cancer showing a correlation with the prognosis, Medical Oncology 28 Suppl 1:S197-203 (2011); Casneuf V F, et al., Expression of SGLT1, Bcl-2 and p53 in primary pancreatic cancer related to survival, Cancer Investigation 26(8):852-859 (2008); Blessing A, et al., Sodium/Glucose Co-transporter 1 Expression Increases in Human Diseased Prostate, J. Cancer Sci. Ther. 4(9):306-312 (2012). As an example, late stage prostate cancers express elevated levels of EGFR and uptake a high amount of glucose (Hernes E., et al., Expression of the epidermal growth factor receptor family in prostate carcinoma before and during androgen-independence, British J. Cancer, 90(2):449-454 (2004); Pu Y S, et al., Epidermal growth factor receptor inhibitor (PD168393) potentiates cytotoxic effects of paclitaxel against androgen-independent prostate cancer cells, Biochemical Pharmacology, 71(6):751-760 (2006); Sherwood E R, et al., Epidermal growth factor-related peptides and the epidermal growth factor receptor in normal and malignant prostate, World J. Urology, 13(5):290-296 (1995); Lee S T, et al., PET in prostate and bladder tumors, Seminars in Nuclear Medicine 42(4):231-246 (2012); Oyama N, et al., The increased accumulation of [18F]fluorodeoxyglucose in untreated prostate cancer, Japanese J. Clinical Oncology, 29(12):623-629 (1999)). A better understanding of the functional relationship between EGFR and SGLT1 may lead to identification of novel therapeutic targets for cancer therapy.
Thus, there is need in the art for methods and compositions that can adequately treat cancer cells resistant to EGFR tyrosine kinase inhibitors.